1. Field of the Invention
The present invention relates to the area of selective protection of identical amino groups in cyclic polyamines, and preferably, relates to an improved process for preparing 1, 1xe2x80x2-[1,4-phenylenebis (methylene)]-bis1,4,8,11-tetraazacyclotetradecane.
2. Description of the Prior Art
J. Med. Chem, Vol. 38, No. 2, pgs. 366-378 (1995) is directed to the synthesis and anti-HIV activity of a series of novel phenylbis(methylene)-linked bis-tetraazamacrocyclic analogs, including 1,1xe2x80x2-[1,4-phenylenebis (methylene)]-bis1,4,8,11-tetraazacyclotetradecane. This compound and its analogs are prepared by: 1) forming the tritosylate of the tetraazamacrocycle; 2) reacting the protected tetraazamacrocycle with an organic dihalide, e.g., dibromo-p-xylene, in acetonitrile in the presence of a base such as potassium carbonate; and 3) de-protecting the bis-tetraazamacrocycle prepared in 2) employing freshly prepared sodium amalgam, concentrated sulfuric acid or an acetic acid/hydrobromic acid mixture to obtain the desired cyclam dimer in the form of a salt.
U.S. Pat. No. 5,047,527 is directed to a process for preparing a mono-functionalized (e.g., monoalkylated) cyclic tetraamine comprising: 1) reacting the unprotected macrocycle with chrominum hexacarbonyl to obtain a triprotected tetraazacycloalkane compound; 2) reacting the free amine group of the triprotected compound prepared in 1) with an organic halide to obtain a triprotected mono-functionalized tetraazacycloalkane compound; and 3) deprotecting the compound prepared in 2) by simple air oxidation to obtain the desired compound.
In addition, the reference discloses alternative methods of tri-protection of cyclic tetraamine employing boron and phosphorous derivatives. These tri-protected intermediates are used in the preparation of linked compounds, including the cyclam dimer 1,1xe2x80x2-[1,4-phenylenebis (methylene)]-bis1,4,8,11-tetraazacyclotetradecane, by reacting with an organic dihalide in a molar ratio of 2:1, followed by deprotection.
Synthetic Communications, 28(15), pgs. 2903-2906, (1998) describes an improved method adopting the above-mentioned phosphorous protection, deprotection sequence to make 1,1xe2x80x2-[1,4-phenylenebis (methylene)]-bis1,4,8,11-tetraazacyclotetradecane.
U.S. Pat. No. 5,606,053 is directed to a process for preparing cyclam dimer 1,1xe2x80x2-[1,4-phenylenebis (methylene)]bis1,4,8,11-tetraazacyclotetradecane. The compound is prepared by: 1) tosylation of tetraamine starting material to obtain an acyclic ditosyl intermediate and an acyclic tritosyl intermediate; 2) separation of the two different tosylation product from step 1), e.g. the ditosyl tetraamine and the tritosyl tetraamine; 3) alkylation of the ditosyl tetraamine with dibromoxylene, followed by tosylation to make hexatosylated acyclic cyclam dimer; 4) alkylation of the tritosyl tetraamine from 1); 5) cyclization of the compound prepared in steps 3) and 4), i.e., the bridged hexatosyl acyclic dimer, by reacting it with three equivalents of ethylene glycol ditosylate; 6) detosylation of the cyclized cyclam dimer by reacting with a mixture of hydrobromic acid and glacial acetic acid to obtain the product in the form of an HBr salt.
U.S. Pat. No. 5,801,281 is directed to an improved process for preparing the cyclam dimer 1,1xe2x80x2-[1,4-phenylenebis (methylene)]-bis1,4,8,11-tetraazacyclotetradecane. The compound is prepared by: 1) reacting the acyclic tetraamine with 3 equivalents of ethyl trifluoroacetate; 2) alkylation of the tri-protected acyclic tetraamine with 0.5 equivalents of dibromoxylene, to obtain the 1,4 phenylene bis-methylene bridged acyclic dimer; 3) hydrolysis to remove the six trifluoroacetyl groups of the compound prepared in step 2); 4) tosylation of the compound prepared in step 3) to obtain the hexatosylated bridged tetraamine dimer; 5) cyclization of the compound in step 4) with ethylene glycol ditosylate to obtain the hexatosylated cyclam dimer; 6) detosylation of the compound prepared in step 5) to obtain the cyclam dimer 1,1xe2x80x2-[1,4-phenylenebis (methylene)]-bis1,4,8,11-tetraazacyclotetradecane in the form of a salt using HBr/HOAc mixture.
U.S. Pat. No. 5,064,956 discloses a process for preparing mono-alkylated polyazamacrocycles by reacting unprotected macrocycle with an electrophile in an aprotic, relatively non-polar solvent in the absence of a base. No example resembling the synthesis of cyclam dimer was provided.
Although the current approaches to 1,1xe2x80x2-[1,4-phenylenebis (methylene)]-bis1,4,8,11-tetraazacyclotetradecane via tri-protection of cyclam or starting from acyclic tetraamine as demonstrated previously are suitable to prepare the compound (supra), they both suffer from the fact that the key step in each process is low yielding. The average yield of tri-protection reported is rarely over 50%. The macrocyclizations are also frequently suffering from lower yields. In addition, the deprotection of tosyl groups is time consuming and requires relatively harsh conditions.
It is known to those skilled in the art that the direct N-1 protection of N-ring nitrogen containing cyclic polyamines, where xe2x80x9cN-1 protectionxe2x80x9d refers to the protection of all but one nitrogen in a cyclic polyamine containing N amines and N equals the number of protectable primary or secondary amines, e.g. cyclam and cyclen (N=4 in both cases), are generally problematic. Protecting groups such as tosyl, mesyl, Boc etc have been tested and vigorously optimized. Nevertheless, the drawbacks of these existing methods are obvious in several general aspects: 1) the low to moderate yield (frequently less than 50%) during the N-1 protection pursued due to the concurrent formation, with relatively great amount, of from N-M (M less than N) to N substituted derivatives; 2) the difficulty in the isolation of the N-1 protected intermediate from the mixture; and 3) in several cases, such as tosyl, the harsh conditions required in the removal of these protecting groups at certain stage of the application.
In particular, the chemistry related to the tri-protection of tetraazamacrocycles such as 1,4,8,11-tetraazacyclotetradecane (cyclam), 1,4,7,10-tetraazacyclododecane (cyclen) and the di-protection of 1,4,7-triazacyclononane are currently under active development in the field. It will be obvious to those skilled in the art that these N-1 protected cyclic polyamines are useful intermediates that will lead to, after necessary manipulation, mono-substituted cyclic amines. Hence these are key intermediates having great potential in the preparation of MRI diagnostic agents (U.S. Pat. No. 5,994,536; U.S. Pat. No. 5,919,431; U.S. Pat. No. 5,871,709; U.S. Pat. No. 5,410,043; U.S. Pat. No. 5,277,895; U.S. Pat. No. 5,132,409; U.S. Pat. No. 4,885,363.) or for the preparation of anti-HIV compounds (U.S. Pat. No. 5,583,131; U.S. Pat. No. 5,698,546; U.S. Pat. No. 5,021,409; and U.S. Pat. No. 6,001,826), or for the preparation of compounds disclosed in PCT WO 2000/45814.
More recently, U.S. Pat. No. 5,705,637 discloses a process for preparing tri-benzylated macrocycles following a macrocyclization/amide reduction sequence. The three benzyl groups are removed eventually to afford mono-substituted cyclen.
For those skilled in the art it will also be obvious that the N-1 protected cyclic macrocyclic polyamines of the present invention are useful, after necessary additional protection deprotection steps, for the preparation of N-1 substituted cyclic polyamines.
Certain unique nitrogen protecting groups other than those described above have been reported and offer from low to excellent selectivity among primary and secondary amines and between two secondary amines.
Tetrahedron Letters Vol. 36. No. 20, pgs 3451-3452, (1995) reported reactions using ethyl trifluoroacetate to selectively protect primary amine in the presence of secondary amine in several linear polyamine compounds.
Tetrahedron Letters Vol. 36. No. 41, pgs 7357-7360, (1995) relates to examples using single equivalent ethyl trifluoroacetate to selectively protect di-primary amines and di-secondary amines. One case involving a six-membered diamine piperazine demonstrated a moderate selectivity of 5.8:1 when one equivalent of ethyl trifluoroacetate is used per equivalent of piperazine. It is noted that treatment of piperazine with excess ethyl trifluoroacetate readily produces more double (full) protected product, thus significantly reduced selectivity.
U.S. Pat. No. 6,080,785 relates to new mono-functionalized ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid and triethylenetetraaminehexaacetic acid derivatives. A linear 1,4,7-triazaheptane was treated with 1.1 equivalents of ethyl trifluoroacetate and produced a mixture of monoamide and diamide at a ratio of 9:1. This mixture was carried further to the next step.
The present invention is based on the discovery that, when certain protecting agents are used to protect cyclic polyamines containing N ring nitrogen (Nxe2x89xa73) with each nitrogen being separated by 2 or more carbon atoms , the rate of reaction will slow down sharply once N-1 nitrogens are protected, even when all of the nitrogens in the cyclic polyamine are originally chemically equivalent. These controlled reactions thus afford, in an excellent yield, the important N-1 protected polyazamacrocycles at high selectivity.
The present invention relates, for example, to efficient high yielding N-1 protection of cyclic polyamines containing a total of N amine nitrogens, where the ring has from 9 to 20 ring members and N is from 3 to 6 amine nitrogens spaced by 2 or more carbon atoms, using fluroronated acid esters and other structurally related protecting agents (formula III). The resultant protected amines prepared by this method are useful intermediates for the preparation of selectively N-substituted protected cyclic polyamines. The protected selectively N-substituted cyclic polyamine is readily deprotected under mild conditions to form selectively N-substituted cyclic polyamines.
More particularly, the current invention discloses, inter alia, the high yielding tri-protection of 1,4,8,11-tetraazacyclotetradecane (cyclam), 1,4,7,10-tetraazacyclododecane (cyclen) and di-protection of 1,4,7-triazacyclononane using agents such as those represented by formula III.
In addition, the present invention provides an extremely efficient and economic process for preparing 1,1xe2x80x2-[1,4-phenylenebis (methylene)]-bis1,4,8,11-tetraazacyclotetradecane from cyclam, by using protecting groups such as, but not limited to, trifluoroacetyl, following a reaction sequence of tri-protection, alkylation and deprotection.
Other aspects of the invention are described throughout the specification and in particular the claims.